Resistance to flavivirus morbidity and mortality in mice is controlled by a single autosomal-dominant allele (Flv). Resistant mice are susceptible to other types of viruses but are resistant to disease induced by all flaviviruses tested to date, including West Nile, Dengue, Japanese encephalitis and tickborne encephalitis viruses. Resistant mice and cell cultures are efficiently infected by flaviviruses but produce lower yields of virus than susceptible mice. The resistant phenotype is constitutively expressed and does not require IFN induction. The FIv locus was mapped to a region on mouse chromosome 5 by recombination studies in mice. An allele of the 2'-5'-oligoadenylate synthetase gene, Oas1b, was identified as FIv using a positional cloning strategy (Perelygin et al., PNAS 99: 9322-9327, 2002). A correlation between genotype and phenotype was observed in 10 mouse strains. Mouse strains that are susceptible to flaviviruses have a C-to-T transition in exon 4 of the gene resulting in a premature stop codon and the expression of a truncated protein. This application proposes the generation of a number of Oas gene knock-in and knockout mouse strains that will be used in studies to address the following questions. (1). Is the Oas1b resistant allele all that is required to confer resistance to flavivirus-induced disease in a susceptible mouse? (2). Does RNase L play a role in the resistance phenotype? (3). Do other mouse Oas1 genes play a role in host defense against flaviviruses? (4). Do different mouse Oas1 genes play unique roles in host defense to specific groups of viruses? (5). Can all of the mouse Oas1 genes be deleted? The strains of transgenic mice generated in this study are not only essential for further studies of the mechanism of Oas1b-mediated resistance to flavivirus-induced disease as well as the study of novel intracellular anti-flaviviral pathways, but they also represent a valuable resource for future studies on innate immune responses to other groups of viruses.